Intermediate clinical endpoints: A bridge between progression‐free survival and overall survival in ovarian cancer trials

Abstract

Ovarian cancer patients are usually diagnosed at an advanced stage, experience recurrence after platinum-based chemotherapy, and eventually develop resistance to chemotherapy. Overall survival (OS), which has improved in recent years as more active treatments have been incorporated into patient care, is regarded as the most clinically relevant endpoint in ovarian cancer trials. However, although there remains a significant need for new treatments that prolong OS further without compromising quality of life, it has become increasingly difficult to detect an OS benefit for investigational treatments because of the use of multiple lines of chemotherapy to treat ovarian cancer. Progression-free survival (PFS), which measures the time to disease progression or death, is unaffected by postprogression therapies but does not evaluate the long-term impact of investigational treatments on tumor biology and responses to future therapies. Recent clinical trials of targeted agents in relapsed ovarian cancer have shown improvements in PFS but not OS, and this is possibly reflective of the long postprogression survival (PPS) period associated with this disease. Intermediate endpoints such as the time to second disease progression or death and the time to second subsequent therapy or death may provide supportive evidence for clinically meaningful PFS improvements and may be used to determine whether these improvements persist beyond the first disease progression and throughout subsequent lines of therapy. For clinical trials that have settings with a long PPS duration and/or involve multiple rounds of postprogression therapy, a primary endpoint of PFS supported by intermediate clinical endpoints and OS may provide a more comprehensive approach for evaluating efficacy.

Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): Long-term survival, impact of ascites, and progression-free survival-2

“…However, it has proven exceptionally difficult to show a statistically significant prolongation of OS with the addition of targeted therapy to standard treatments in patients with ovarian cancer [10][11][12][13][14][15][16][17][18][26][27][28]. Potential confounding factors for OS include the long postprogression survival period, the administration of multiple postprogression therapies, and the potential for postprogression crossover [27,29]. In the TRINOVA-1 study, 47% of patients had received at least two lines of postprogression therapy, and 14% received an antiangiogenic therapy after progression.…”

“…HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PFS-2, time to second progression event; TSST, time to second subsequent treatment. (8) 101 (22) Treatment-emergent adverse events with ≥5% difference in incidence between arms Localized edema 122 (27) One approach to addressing these challenges suggested by the EMA is to assess the durability of treatment effect by evaluating postprogression endpoints such as PFS-2 and time to second subsequent therapy (TSST) [27,30]. The TRINOVA-1 study is among the first to demonstrate that an antiangiogenic therapy significantly delayed the time to second progression (i.e.…”

Ovarian cancer

“…One challenge for the development of new therapies in ovarian cancer is the approval mechanisms of the FDA and EMA. Demonstrating an improvement of overall survival is a requirement for regulatory approval, but is difficult to demonstrate in ovarian cancer; explanations for this are not fully understood, but possibly include the use of active study agents after disease progression, which dilutes the effect of the active agent on overall survival but not on PFS (243,244). Additionally, the lack of subclassification of histologic subtypes for clinical trial eligibility might have diluted the efficacy of some therapeutic agents, such as bevacizumab and also because no biomarker currently exists to select patients to receive this therapy.…”

Resisting RECIST—Uniformity Versus Clinical Validity

“…6,7 With the increasing use of PFS as the primary endpoint in clinical trials, there is a pressing need to include additional measures that support PFS to ensure it is a clinically meaningful endpoint. 8,9 The generalizability of the results of this survey is constrained by the small sample size and format of this research. No clear denominator was collected to determine the likely response rate to these surveys, but it is estimated to be less than 30%.…”